This Program Project Grant focuses on development of effective therapies for CML, based upon the emerging understanding of its molecular pathophysiology and also its unique susceptibility to biologic therapies, allotransplantation and immunotherapeutic approaches. The ultimate goal is to improve the current paradigms for curative treatment of this disease. This program has had continuous funding for the last 13 years. The program involves 9 projects and 6 cores are proposed forming a translational research program with the goal of advancing the treatment of chronic myelogenous leukemia. Projects 0020 and 0006 involve clinical investigations. Project 0020 studies chemo-biologic therapies designed to induce cytogenetic and molecular remission. Project 0006 involves hematopoietic transplantation focusing on imatinib-drug interactions, enhancement of graft-vs-leukemia and antigen specific immunotherapy to improve the therapeutic index of the preparative regimen. Projects 0021 and 0022 investigate strategies for development of T-cell based immunotherapy to induce graft-vs-leukemia effects without GVHD. Project 0021 involves induction of antigen specific antileukemic immune reactivity. Project 0022 involves induction of graft-vs-leukemia using lymphocytes transduced with Herpes virus thymidine kinase, a suicide gene, which allows abrogation of graft-vs-host disease; a novel vector and transduction system is proposed to preserve lymphocyte function and alloreactivity. Project 0023 evaluates the mechanisms of resistance to imatinib mesylate therapy and potential therapeutic interventions to circumvent resistance. Project 0018 focuses on novel approaches to facilitate engraftment and prevent GVHD in haploidentical transplants. Project 0024 examines molecular mechanisms of bcr-abl oncogenesis including the role of bcr and secreted cell death factors, lipocalins. Project 0012 evaluates epigenetic alterations in CML addressing whether clinical subtype and response to therapy can be classified by the epigenotype of the malignant cells or expression of chromatin modifying genes, whether the epigenotype be used to predict response to therapy. Project 0025 evaluates genetically modified mesenchymal stem cells which home to the marrow for selective delivery of therapeutic cytokines to the microenvironment of the leukemia. Cores are included: Core A is the administrative core. Core 9003 is biostatistics. Core 9008 is the immunology core, performing studies of antileukemia immunity and immune reconstitution. Core 9006 performs cell culture and clonogenic assays. Core 9009 is the cell collection and distribution core. Core 9010 is the GMP Cell Laboratory Core, required for cell processing for human clinical trials.